Process for the preparation of diamine intermediates useful in the synthesis of HIV protease inhibitors

ABSTRACT

The present invention provides a process for the preparation of compounds of formula (V) below, and analogs thereof, which are useful as intermediates for the synthesis of HIV protease inhibitors, including cyclic ureas. ##STR1##

CROSS-REFERENCE TO EARLIER FILED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 08/197,630 filed Feb. 16, 1994. The disclosure of this earlierfiled application is hereby incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to compounds which are useful as intermediatesfor the synthesis of human immunodeficiency virus (HIV) proteaseinhibitors, including cyclic carbonyls. This invention also relates tomethods for the synthesis of HIV protease inhibitors, including cycliccarbonyls.

BACKGROUND OF THE INVENTION

Many nonpeptide C-2 symmetric and pseudosymmetric compounds have showngood biological activity as human immunodeficiency virus (HIV) proteaseinhibitors. Compounds and methods for their preparation are increasinglyfound in the literature. (Kempf et al., J. Org. Chem. 57, 5692-5700(1992); Livermore et al., J. Med. Chem. 36, 3784-3794 (1993); Lam etal., Science 263, 380-384 (1994); Jadhav et al., WO 93/07128; EP402,646; Dreyer et al., Biochemistry 32, 937-47 (1993); Sowin et al. WO93/23361; Jadhav et al., Bioorganic & Med. Chem. Lett. 2, 353-356(1992); Jadhav et al., U.S. Pat. No. 5,294,720.

U.S. Pat. No. 5,294,720 and European Patent Application 402,646 A1describe the synthesis of diamine ##STR2## via coupling of aldehydesderived from suitably protected aminoacids.

Baker and Condon, J. Org. Chem. 1993, 58, 3277-3284, disclose a methodfor the preparation of linear diaminodiols from(-)-2,3-isopropylidene-D-threitol shown below. ##STR3##

European Patent Application 402,646 A1 also describes the synthesis ofbisoxime (C) from the bisamide (B). This product was obtained inrelatively poor yields and no further transformations were disclosed.##STR4##

Lam et al., PCT International Publication Number WO 93/07,128 disclosescyclic carbonyl compounds and derivatives thereof which are useful ashuman immunodeficiency virus (HIV) protease inhibitors for the treatmentof HIV infection. The compounds disclosed in WO 93/07128 include cyclicHIV protease inhibitor compounds of the formula below where W may be--N(R²²)C(═O)N(R²³)--. ##STR5##

The above methods for the preparation of linear diaminodiols userelatively expensive starting materials and toxic reagents.

The present invention provides a improved synthetic processes for thepreparation of diamine intermediates useful for the synthesis of HIVprotease inhibitors. The process of the present inventions usesinexpensive chiral raw materials and environmentally nonhazardousreagents.

None of the above-cited references describe the methods of the presentinvention for the synthesis of diamines useful as intermediates for thesynthesis of HIV protease inhibitors.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation ofcompounds of formula (V) below, which are useful as intermediates forthe synthesis of HIV protease inhibitors, including cyclic ureas.

The present invention provides a process for the preparation ofcompounds of formula (V): ##STR6## or intermediates for the synthesis ofcompounds of formula (V), wherein R⁴, R⁷, R¹ and R² are defined below,said process comprising one or more of the following steps:

(1) contacting a compound of formula (I): ##STR7## in an aprotic solventwith a carboxyl activating agent, followed by reaction with aN,O-dialkylhydroxylamine of formula R⁶ NHOR⁵, to form a compound offormula (II): ##STR8## wherein R¹, R², R⁵, and R⁶ are defined below;

(2) contacting a compound of formula (II) in an aprotic solvent with anucleophilic organometallic reagent being suitable for the addition of aR⁴ - or R⁷ -substituent to amides of the structure of compound (II),thereby to form a compound of formula (III): ##STR9## wherein R¹, R², R⁴and R⁷ are defined below;

(3) reacting a compound of formula (III) in a protic solvent with ahydroxylamine of formula NH₂ OR³, to form a compound of formula (IV):##STR10## wherein R¹, R², R⁴, R⁷, and R³ are defined below;

(4) contacting a compound of formula (IV) with a reducing agent toeffect the conversion of the oxime groups in the compound of formula(IV) to amine groups, to obtain a compound of formula (V).

DETAILED DESCRIPTION OF THE INVENTION

There is provided by this invention a process for preparation ofcompounds of formula (V): ##STR11## or intermediates for the synthesisof compounds of formula (V), said compounds being useful asintermediates for the preparation of HIV protease inhibitors, includingcyclic urea HIV protease inhibitors, wherein:

R¹ and R² are independently: H, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₆ -C₁₀aryl, C₇ -C₁₄ arylalkyl, C₁ -C₄ haloalkyl, C₃ -C₇ cycloalkyl, or can betaken together to be keto;

alternatively, R¹ and R² can be taken together with the carbon to whichthey are attached to form a 3-7 membered saturated carbocyclic ringsystem;

R⁴ and R⁷ are independently:

C₁ -C₈ alkyl substituted with 0-3 R¹¹ ;

C₂ -C₈ alkenyl substituted with 0-3 R¹¹ ;

C₂ -C₈ alkynyl substituted with 0-3 R¹¹ ;

a C₃ -C₁₄ carbocyclic ring system substituted with 0-3 R¹¹ or 0-3 R¹² ;

a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-2 R¹² ;

R¹¹ is selected from one or more of the following:

H, keto, halogen, cyano, --CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, --OR¹³, C₁ -C₄alkyl, C₂ -C₄ alkenyl, C₃ -C₆ cycloalkylmethyl, benzyl, phenethyl,phenoxy, benzyloxy, nitro, C₇ -C₁₀ arylalkyl, C₃ -C₆ cycloalkoxy, C₁ -C₄alkyl substituted with --NR¹³ R¹⁴, C₁ -C₄ hydroxyalkyl, methylenedioxy,ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy,2-(1-morpholino)ethoxy, or azido;

C₃ -C₁₀ cycloalkyl substituted with 0-2 R¹² ;

C₁ -C₄ alkyl substitued with 0-2 R¹² ;

aryl(C₁ -C₃ alkyl)-, substituted with 0-2 R¹² ;

C₂ -C₆ alkoxyalkyl-, substituted with 0-2 R¹² ;

a C₅ -C₁₄ carbocyclic residue substituted with 0-3 R¹² ; or

a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-3 R¹² ;

R^(11A) is:

H, halogen, cyano, --CH₂ N(R^(13A))R(^(14A)), --N(R^(13A))R(^(14A)),--OH, C₂ -C₆ alkoxyalkyl, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₃ -C₁₀cycloalkyl, C₃ -C₆ cycloalkylmethyl, benzyl, phenethyl, phenoxy,benzyloxy, nitro, C₇ -C₁₀ arylalkyl, C₃ -C₆ cycloalkoxy, C₁ -C₄ alkylsubstituted with --NH₂, C₁ -C₄ hydroxyalkyl, methylenedioxy,ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy,2-(1-morpholino)ethoxy, azido, aryl(C₁ -C₃ alkyl), a C₅ -C₁₄ carbocyclicresidue; or a 5- to 10-membered heterocyclic ring system containing 1 to4 heteroatoms independently selected from oxygen, nitrogen or sulfur,said heterocyclic ring system substituted with 0-3 R^(12A).

R¹², when a substituent on carbon, is:

phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro,cyano, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl, C₇ -C₁₀arylalkyl, C₁ -C₄ alkoxy, C₃ -C₆ cycloalkoxy, --OR¹³, C₁ -C₄ alkylsubstituted with --NR¹³ R¹⁴, --NR¹³ R¹⁴, C₂ -C₆ alkoxyalkylene, C₁ -C₄hydroxyalkyl, methylenedioxy, ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄haloalkoxy, 2-(1-morpholino) ethoxy, or

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from oxygen, nitrogen or sulfur;

or R¹² may be a 3- or 4- carbon chain attached to adjacent carbons onthe ring to form a fused 5- or 6-membered ring, said 5- or 6- memberedring being optionally substituted on the aliphatic carbons with halogen,C₁ -C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, --NR¹³ R¹⁴ ;

R¹² when a substituent on nitrogen, is:

phenyl, benzyl, phenethyl, hydroxy, C₁ -C₄ hydroxyalkyl, C₁ -C₄ alkoxy,C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl --CH₂ NR¹³ R¹⁴,--NR¹³ R¹⁴, C₂ -C₆ alkoxyalkyl, C₁ -C₄ haloalkyl;

R^(12A), when a substituent on carbon, is:

phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro,cyano, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl, C₇ -C₁₀arylalkyl, C₁ -C₄ alkoxy, C₃ -C₆ cycloalkoxy, --OR^(13a), C₁ -C₄ alkylsubstituted with --NH₂, --NH₂, --NHMe, C₂ -C₆ alkoxyalkyl, C₁ -C₄hydroxyalkyl, methylenedioxy, ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄haloalkoxy, 2-(1-morpholino)ethoxy,

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from oxygen, nitrogen or sulfur;

or R^(12A) may be a 3- or 4- carbon chain attached to adjacent carbonson the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons withhalogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, or --NH₂ ;

R^(12A), when a substituent on nitrogen, is:

phenyl, benzyl, phenethyl, hydroxy, C₁ -C₄ hydroxyalkyl, C₁ -C₄ alkoxy,C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl, --CH₂ NH₂,--NH₂, C₂ -C₆ alkoxyalkyl, or C₁ -C₄ haloalkyl;

R¹³ is selected from:

H;

phenyl substituted with 0-3 R^(11A) ;

benzyl substituted with 0-3 R^(11A) ;

C₁ -C₆ alkyl substituted with 0-3 R^(11A) ;

C₂ -C₄ alkenyl substituted with 0-3 R^(11A) ;

C₃ -C₆ alkoxyalkyl substituted with 0-3 R^(11A) ;

an amine protecting group when R¹³ is bonded to N;

a hydroxy protecting group when R¹³ is bonded to O;

R¹⁴ is selected from: hydrogen; hydroxy; C₁ -C₆ alkoxy; C₂ -C₆ alkenyl;phenyl; benzyl; an amine protecting group when R¹⁴ is bonded to N; ahydroxy protecting group when R¹⁴ is bonded to O; or C₁ -C₆ alkylsubstituted with 0-3 groups selected from OH, C₁ -C₄ alkoxy, halogen,NH₂, --NH(C₁ -C₄ alkyl);

R¹³ and R¹⁴ can alternatively join to form --(CH₂)₄ --, --(CH₂)₅ --,--CH₂ CH₂ N(R¹⁵)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --;

R^(13A) and R^(14A) are independently selected from: H, C₁ -C₆ alkyl;

R^(13A) and R^(14A) can alternatively join to form --(CH₂)₄ --, --(CH₂)₅--, --CH₂ CH₂ N(R¹⁵)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --;

R¹⁵ is H or CH₃ ;

m is 0, 1 or 2;

said process comprising one or more of the following steps:

step (1) (amide formation): (a) contacting a compound of formula (I):##STR12## in an aprotic solvent with a carboxyl activating agent,followed by; (b) addition of of a N,O-dialkylhydroxylamine of formula R⁶NHOR⁵, to form a compound of formula (II): ##STR13## wherein R¹ and R²are defined as above and R⁵ and R⁶ are independently C₁ -C₄ alkyl orbenzyl;

step (2) (ketone formation): contacting a compound of formula (II) in anaprotic solvent with a nucleophilic organometallic reagent, saidnucleophilic organometallic reagent being suitable for the addition of aR⁴ - or R⁷ - substituent to amides of the structure of compound (II), toform a compound of formula (III): ##STR14## wherein R¹, R², R⁴ and R⁷are defined as above;

step (3) (oxime formation): reacting a compound of formula (III) in aprotic solvent with an hydroxylamine of formula NH₂ OR³, to form acompound of formula (IV): ##STR15## wherein R¹, R², R⁴ and R⁷ aredefined as above and R³ is hydrogen, C₁ -C₆ alkyl, benzyl, arylcarbonylor (C₁ -C₆ alkyl)carbonyl;

step (4) (amine formation): contacting a compound of formula (IV) in asuitable solvent with a reducing agent to effect the conversion of theoxime groups in the compound of formula (IV) to amine groups, to obtaina compound of formula (V).

The present invention includes a process for the preparation ofcompounds of formula (IV): ##STR16## said process comprising one or moreof the following steps:

step (1) (amide formation): (a) contacting a compound of formula (I):##STR17## in an aprotic solvent with a carboxyl activating agent,followed by; (b) addition of a N,O-dialkylhydroxylamine of formula R⁶NHOR⁵, to form a compound of formula (II): ##STR18## wherein R¹ and R²are defined as above and R⁵ and R⁶ are independently C₁ -C₄ alkyl orbenzyl;

step (2) (ketone formation): contacting a compound of formula (II) in anaprotic solvent with a nucleophilic organometallic reagent, saidnucleophilic organometallic reagent being suitable for the addition of aR⁴ - or R⁷ - substituent to amides of the structure of compound (II), toform a compound of formula (III): ##STR19## wherein R¹, R², R⁴ and R⁷are defined as above;

step (3) (oxime formation): reacting a compound of formula (III) in aprotic solvent with an hydroxylamine of formula NH₂ OR³, to form acompound of formula (IV): ##STR20## wherein R¹, R², R⁴ and R⁷ aredefined as above and R³ is hydrogen, C₁ -C₆ alkyl, benzyl, arylcarbonylor (C₁ -C₆ alkyl)carbonyl.

The present invention also provides a process for the preparation ofcompounds of formula (III): ##STR21## said process comprising one ormore of the following steps:

step (1) (amide formation): (a) contacting a compound of formula (I):##STR22## in an aprotic solvent with a carboxyl activating agent,followed by; (b) addition of a N,O-dialkylhydroxylamine of formula R⁶NHOR⁵, to form a compound of formula (II): ##STR23## wherein R¹ and R²are defined as above and R⁵ and R⁶ are independently C₁ -C₄ alkyl orbenzyl;

step (2) (ketone formation): contacting a compound of formula (II) in anaprotic solvent with a nucleophilic organometallic reagent, saidnucleophilic organometallic reagent being suitable for the addition of aR⁴ - or R⁷ - substituent to amides of the structure of compound (II), toform a compound of formula (III): ##STR24## wherein R¹, R², R⁴ and R⁷are defined as above.

There is also provided by this invention a process for the preparationof compounds of formula (II): ##STR25## said process comprising the stepof:

step (1) (amide formation): (a) contacting a compound of formula (I):##STR26## in an aprotic solvent with a carboxyl activating agent,followed by; (b) addition of a N,O-dialkylhydroxylamine of formula R⁶NHOR⁵, to form a compound of formula (II): ##STR27## wherein R¹ and R²are defined as above and R⁵ and R⁶ are independently C₁ -C₄ alkyl orbenzyl.

Preferred in the present invention is a process as described abovewherein:

R¹ and R² are methyl, ethyl, or can be taken together with the carbon towhich they are attached to form cyclopentyl;

R⁴ and R⁷ are C₁ -C₈ alkyl substituted with 0-1 R¹¹ ;

R¹¹ is

H; halogen; --OR¹³ ;

C₃ -C₁₀ cycloalkyl substituted with 0-2 R¹² ;

aryl substituted with 0-2 R¹² ; or

a heterocyclic ring system selected from pyridyl, pyrimidinyl,triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl,oxazolidinyl, said heterocyclic ring system being substituted with 0-2R¹² ;

R¹², when a substituent on carbon, is selected from one or more of thefollowing:

benzyloxy, halogen, methyl, C₁ -C₄ alkoxy, CF₃, 2-(1-morpholino)ethoxy,cyano, C₃ -C₆ cycloalkoxy, C₁ -C₄ alkyl substituted with --NR¹³ R¹⁴,--NR¹³ R¹⁴ ;

R¹², when a substituent on nitrogen, is methyl;

R¹³ is H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, or benzyl;

R¹⁴ is H, CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₂ -C₄ alkenyl, or benzyl;

R¹³ and R¹⁴ can alternatively join to form --(CH₂)₄ --, --(CH₂)₅ --,--CH₂ CH₂ N(R¹⁵)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --.

Further preferred in the present invention is a process as describedabove wherein:

R¹ and R² are methyl;

R⁴ and R⁷ are benzyl, fluorobenzyl, pyrrolylmethyl, methoxybenzyl,isobutyl, n-octyl, n-hexyl, dimethylaminobenzyl, thienylmethyl,pyridylmethyl, or naphthylmethyl.

The present invention also provides compounds of formula (II): ##STR28##wherein: R⁵ and R⁶ are independently C₁ -C₄ alkyl or benzyl; and

R¹ and R² are independently: H, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₆ -C₁₀aryl, C₇ -C₁₄ arylalkyl, C₁ -C₄ haloalkyl, C₃ -C₇ cycloalkyl, or can betaken together to be keto, or, alternatively, R¹ and R² can be takentogether with the carbon to which they are attached to form a 3-7membered saturated carbocyclic ring system.

The processes of the present invention are useful for the preparation ofcompounds useful as intermediates for the synthesis of cyclic HIVprotease inhibitors, including cyclic urea HIV protease inhibitors. Suchcyclic HIV protease inhibitors are disclosed in copending commonlyassigned U.S. patent application Ser. No. 08/197,630, Lam et al., filedFeb. 16, 1994 and Lam et al., PCT International Publication Number WO93/07,128, the disclosures of which are incorporated herein byreference. Such cyclic HIV protease inhibitors are useful for theinhibition of HIV and the treatment of HIV infection. Such cyclic HIVprotease inhibitors are also useful for the inhibition of HIV in an exvivo sample containing HIV or expected to be exposed to HIV. Thus, suchcyclic HIV protease inhibitors may be used to inhibit HIV present in abody fluid sample (for example, a serum or semen sample) which containsor is suspected to contain or be exposed to HIV. Such cyclic HIVprotease inhibitors are also useful as standard or reference compoundsfor use in tests or assays for determining the ability of an agent toinhibit viral replication and/or HIV protease, for example in apharmaceutical research program. Thus, such cyclic HIV proteaseinhibitors may be used as a control or reference compound in such assaysand as a quality control standard. Such cyclic HIV protease inhibitorsmay be provided in a commercial kit or container for use as suchstandard or reference compound. Since such cyclic HIV proteaseinhibitors exhibit specificity for HIV protease, they may also be usefulas diagnostic reagents in diagnostic assays for the detection of HIVprotease. Thus, inhibition of the protease activity in an assay by sucha cyclic HIV protease inhibitor would be indicative of the presence ofHIV protease and HIV virus.

The compounds of formula (I) to (V) of the present invention contain acyclic hydroxyl protecting group --OC(R¹)(R²)O--. As used herein, theterm "cyclic hydroxyl protecting group" refers to any group known in theart of organic synthesis for the protection of 1,2-diol groups. Suchprotecting groups include, but are not limited to, those listed inGreene and Wuts, "Protective Groups in Organic Synthesis", John Wiley &Sons, New York (1991), the disclosure of which is hereby incorporated byreference. The 1,2-diol protecting groups can include, but are notlimited to cyclic acetals (ketals), cyclic carbonates and cyclic orthoesters. Exemplary are methylene acetal, ethylidene acetal,2,2,2-trichloroethylidene acetal, acetonide, cycloheptylidene ketal,cyclopentylidene ketal, cyclohexylidene ketal, benzylidene acetal,phenanthrylidene, methoxymethylene acetal, dimethoxy methylene orthoester, and cyclic carbonates.

The following terms and abbreviations are used herein and are defined asfollows. The abbreviation "THF" as used herein means tetrahydrofuran.The abbreviation "DIBAl" means diisobutylaluminum hydride. Theabbreviation "RaNi" means Raney nickel. The abbreviation "LAH" meanslithium aluminum hydride. The abbreviation "1,1'-CDI" means1,1'-carbonyldiimidazole. The abbreviation "Bn" means benzyl. Theabbreviation "BOC" means t-butyl carbamate. The abbreviation "CBZ" meansbenzyl carbamate.

The reactions of the synthetic methods claimed herein are carried out insuitable solvents which may be readily selected by one of skill in theart of organic synthesis, said suitable solvents generally being anysolvent which is substantially nonreactive with the starting materials(reactants), the intermediates, or products at the temperatures at whichthe reactions are carried out, i.e., temperatures which may range fromthe solvent's freezing temperature to the solvent's boiling temperature.Depending on the particular reaction step, suitable solvents for aparticular reaction step may be selected and may include protic oraprotic solvents, including but not limited to polar aprotic organicsolvents. Depending on the particular reaction step, suitable solventsfor a particular reaction step may be selected and may include, but arenot limited to, toluene, pyridine, dimethylsulfoxide (DMSO),N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), diethylether, benzene, tetrahydrofuran, ethanol, water, methylene chloride,ethylacetate, diethyl ether, benzene, or tetrahydrofuran. Suitablesolvents may include chlorinated organic solvents which include, but arenot limited to, chloroform, methylene chloride, tetrachloroethane, butylchloride and dichloroethane. Suitable non-chlorinated organic solventsmay include, but are not limited to tetrahydrofuran (THF), diethylether, or toluene.

Suitable protic solvents may include, by way of example and withoutlimitation, water, methanol, and ethanol.

Suitable aprotic solvents may include, by way of example and withoutlimitation, dimethylformamide (DMF), dimethylacetamide (DMAC),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),tetrahydrofuran (THF), methylene chloride, dimethoxyethane, ether, orhexanes.

As used herein, the term "carboxyl activating agent" means any reagentor combination of reagents that will activate a carboxylic acid forformation of an amide bond. Exemplary carboxyl activating agentsinclude, by way of example and without limitation,1,1!-carbonyldiimidazole, N,N-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiiide hydrochloride, thionylchloride, oxalyl chloride, and isobutylchloroformate. Some of thesereagents (such as N,N-dicyclohexylcarbodiimide) can be enhanced by theaddition of 1-hydroxybenzotriazole.

Carboxyl activating agents include any agent or combination of agentswhich will effect the formation of an activated carboxyl group and/orany such agent as commonly used in the art of protein or syntheticorganic chemistry to effect the formation of peptide or amide bonds.Such agents include, by way of example and without limitation, thoselisted in Gross and Meienhofer, "The Peptides: Analysis, Synthesis,Biology, Vol. 1", Academic Press, New York (1979), the disclosure ofwhich is hereby incorporated by reference. Such agents include, but arenot limited to, anhydrides, azides, cyanides, carbodiimides, arylesters, carbonyldiimidazole, phosgene, oxalylchloride, thionylchloride,thionylbromide, and alcohols. In general, suitable carboxyl activatingagents include, but are not limited to:N-ethyloxycarbonyl-2-ethyloxy-1,2-dihydroquinoline (EEDQ),N-isobutyloxycarbonyl-2-isobutyloxycarbonyl-1,2-dihydroquinoine (IIDQ),or an alkyl chlorocarbonate, such as isobutyl chlorocarbonate, whichyield mixed anhydride activated carboxyl groups; diphenylphosphorazidatewhich yields azide activated carboxyl groups; and carbonyldiimidazole,ethoxyacetylene, or dicyclohexylcarbodiimide (the latter two preferrablyreacted in the presence of 1-hydroxybenzotriazole orN-hydroxysuccinimide) which yield active ester activated carboxylgroups.

As used herein, the term "nucleophilic organometallic reagent" or"organometallic reagent" means any organometallic reagent that can add aR⁴ - or R⁷ - substituent to amides of the structure of compound (II) toyield a compound of formula (III). Such organometallic reagent may berepresented by the formula R⁴ --M or R⁷ --M, where M is a suitable metalor metal halide, for example, lithium, magnesium halide, zinc, copper,or other suitable metallic group, as is understood in the art of organicsynthesis. Exemplary nucleophilic organometallic reagents include, byway of example and without limitation: benzyllithium, n-butyllithium,sec-butyllithium, tert-butyllithium, methylmagnesium bromide,vinyllithium, allyllithium, ethyllithium, phenylthiomethyllithium,2-furyllithium, butynyllithium, benzylmagnesium chloride, andphenylmagnesium chloride, and substituted derivatives thereof.

As used herein, the term "reducing agent" means any reagent and/orconditions or combinations of such reagents and/or conditions that maybe used to convert an oxime group to an amine. Exemplary oxime reducingagents include, by way of example and without limitation:diisobutylaluminum hydride, lithium aluminum hydride, borane, and Raneynickel and hydrogen.

Such reducing agents include those listed in March, "Advanced OrganicChemistry: Reactions, Mechanisms and Structure" 3rd Edition, John Wiley& Sons, New York (1985), the disclosure of which is hereby incorporatedby reference. Reducing agents include, but are not limited to, lithiumaluminum hydride (LAH), AlH₃, diisobutyl aluminum hydride (DIBAL-H),NaAlEt₂ H₂, sodium bis(2-methoxyethoxy)aluminum hydride (RED-AL®).

As used herein, the term "amine protecting group" (or "N-protected")refers to any group known in the art of organic synthesis for theprotection of amine groups. Such amine protecting groups include thoselisted in Greene and Wuts, "Protective Groups in Organic Synthesis" JohnWiley & Sons, New York (1991) and "The Peptides: Analysis, Synthesis,Biology, Vol. 3, Academic Press, New York (1981), the disclosure ofwhich is hereby incorporated by reference. Any amine protecting groupknown in the art can be used. Examples of amine protecting groupsinclude, but are not limited to, the following: 1) acyl types such asformyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromaticcarbamate types such as benzyloxycarbonyl (Cbz) and substitutedbenzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types suchas tert-butyloxycarbonyl (Boc), ethoxycarbonyl,diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilanesuch as trimethylsilane; and 7) thiol containing types such asphenylthiocarbonyl and dithiasuccinoyl.

Amine protecting groups may include, but are not limited to thefollowing:2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothio-xanthyl)]methylcarbamate; 2-trimethylsilylethyl carbamate; 2-phenylethyl carbamate;1,1-dimethyl-2,2-dibromoethyl carbamate; 1-methyl-l-(4-biphenylyl)ethylcarbamate; benzyl carbamate; p-nitrobenzyl carbamate;2-(p-toluenesulfonyl)ethyl carbamate; m-chloro-p-acyloxybenzylcarbamate; 5-benzyisoxazolylmethyl carbamate; p-(dihydroxyboryl)benzylcarbamate; m-nitrophenyl carbamate; o-nitrobenzyl carbamate;3,5-dimethoxybenzyl carbamate; 3,4-dimethoxy-6-nitrobenzyl carbamate;N'-p-toluenesulfonylaminocarbonyl; t-amyl carbamate; p-decyloxybenzylcarbamate; diisopropylmethyl carbamate; 2,2-dimethoxycarbonylvinylcarbamate; di(2-pyridyl)methyl carbamate; 2-furanylmethyl carbamate;phthalimide; dithiasuccinimide; 2,5-dimethylpyrrole; benzyl;5-dibenzylsuberyl; triphenylmethyl; benzylidene; diphenylmethylene; ormethanesulfonamide.

As used herein, the term "hydroxy protecting group" (or "O-protected")refers to any group known in the art of organic synthesis for theprotection of hydroxyl groups. Such protecting groups include thoselisted in Greene and Wuts, "Protective Groups in Organic Synthesis",John Wiley & Sons, New York (1991), the disclosure of which is herebyincorporated by reference. The hydroxy protecting groups are base-stableand can include, but are not limited to acyl types, aromatic carbamatetypes and alkyl types. Exemplary are methyl, methoxymethyl (MOM),methylthiomethyl, benzyloxymethyl, t-butoxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl,tetrahydrofuranyl, t-butyl, triphenylmethyl, trimethylsilyl,triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, pivaloate orN-phenylcarbamate.

Suitable hydroxy protecting groups may include the following protectinggroups as ethers: tetrahydropyranyl, triphenylmethyl, benzyl,tetrahydrofuranyl, allyl, methoxymethyl (MOM), benzyloxymethyl,p-methoxybenzyloxymethyl, 2-trimethylsilylethoxymethyl (SEM),t-butoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl,trichloroethoxymethyl, t-butyl, p-methoxybenzyl, t-butyldimethylsilyl,o-nitrobenzyl, p-methoxyphenyldiphenylmethyl, p-nitrobenzyl,triisopropylsilyl, t-butyldiphenylsilyl.

Conditions to remove tetrahydropyranyl, triphenylmethyl,tetrahydrofuranyl, methoxymethyl, benzyloxymethyl,p-methoxybenzyloxymethyl, 2-trimethylsilylethoxymethyl, t-butoxymethyl,methylthiomethyl, 2-methoxyethoxymethyl, trichloroethoxymethyl, t-butyl,p-methoxyphenyldiphenylmethyl, may include: (a) 1-4M HCl in anhydrous oraqueous methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, ordiethyl ether; (b) 1-4M H2SO4 in anhydrous or aqueous methanol, ethanol,isopropanol, tetrahydrofuran, dioxane, or diethyl ether; (c) polystyrenesulfonic acid resin in anhydrous or aqueous methanol, ethanol,isopropanol, tetrahydrofuran, dioxane, or diethyl ether; (d) 10-100%trifluoroacetic acid in dichloromethane; or (e) p-toluenesulfonic acidor camphorsulfonic acid in anhydrous or aqueous methanol, ethanol,isopropanol.

Conditions to remove benzyl, benzyloxymethyl, p-methoxybenzyloxymethyl,p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl are: hydrogenolysis in thepresence of 1-17% palladium on carbon, or palladium black. Conditions toremove o-nitrobenzyl group include irradiation of the compound at 320 nmwavelength for 5-60 minutes.

Conditions to remove 2-trimethylsilylethoxymethyl, t-butyldimethylsilyl,triisopropylsilyl, t-butyldiphenylsilyl may include: treatment of thecompound with tetrabutylammonium fluoride; or hydrogen flouride pyridinecomplex in THF, DMF or dimethylpropyleneurea.

Conditions to remove allyl may include: isomerization of the allyl etherwith [Ir(COD) (Ph₂ MeP)₂ ]PF₆ or (Ph₃ P)₃ RhCl in tetrahydrofuran,diethyl ether or dioxane followed by hydrolysis with aqueous HgCl₂.

All of the above mentioned deprotection reactions may be carried out attemperetaures ranging from 0 degree C. to a solvent reflux.

The compounds herein described may have asymmetric centers. Unlessotherwise indicated, all chiral, diastereomeric and racemic forms areincluded in the present invention. Geometric isomers of C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. It will be appreciated that compounds of the presentinvention contain asymmetrically substituted carbon atoms, and may beisolated in optically active or racemic forms. It is well known in theart how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis, from optically active starting materials.All chiral, diastereomeric, racemic forms and all geometric isomericforms of a structure are intended, unless the specific stereochemistryor isomer form is specifically indicated.

When any variable (for example, but not limited to, R¹¹ and R¹²) occursmore than one time in any constituent or in any formula, its definitionon each occurrence is independent of its definition at every otheroccurrence. Thus, for example, if a group is shown to be substitutedwith 0-2 R¹¹, then said group may optionally be substituted with up totwo R¹¹ and R¹¹ at each occurrence is selected independently from thedefined list of possible R¹¹.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. By stable compound orstable structure it is meant herein a compound that is sufficientlyrobust to survive isolation to a useful degree of purity from a reactionmixture.

The term "substituted", as used herein, means that one or more hydrogenon the designated atom is replaced with a selection from the indicatedgroup, provided that the designated atom's normal valency is notexceeded, and that the substitution results in a stable compound.

As used herein, "alkyl" is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms; "haloalkyl" is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morehalogen (for example --C_(v) F_(w) where v=1 to 3 and w=1 to (2v+1));"alkoxy" represents an alkyl group of indicated number of carbon atomsattached through an oxygen bridge; "cycloalkyl" is intended to includesaturated ring groups, including mono-, bi- or poly-cyclic ring systems,such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl and cyclooctyl; and "biycloalkyl" is intended to includesaturated bicyclic ring groups such as [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),[2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended to includehydrocarbon chains of either a straight or branched configuration andone or more unsaturated carbon-carbon bonds which may occur in anystable point along the chain, such as ethenyl, propenyl, and the like;and "alkynyl" is intended to include hydrocarbon chains of either astraight or branched configuration and one or more triple carbon-carbonbonds which may occur in any stable point along the chain, such asethynyl, propynyl and the like.

"Alkylcarbonyl" is intended to include an alkyl group of an indicatednumber of carbon atoms attached through a carbonyl group to the residueof the compound at the designated location. "Alkylcarbonylamino" isintended to include an alkyl group of an indicated number of carbonatoms attached through a carbonyl group to an amino bridge, where thebridge is attached to the residue of the compound at the designatedlocation. "Alkylcarbonyloxy" is intended to include an alkyl group of anindicated number of carbon atoms attached to a carbonyl group, where thecarbonyl group is attached through an oxygen atom to the residue of thecompound at the designated location.

"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, andiodo; and "counterion" is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate, and thelike.

As used herein, "aryl" or "aromatic residue" is intended to mean phenylor naphthyl; the term "arylalkyl" represents an aryl group attachedthrough an alkyl bridge. By way of examples: the term "C₇ -C₁₀arylalkyl" is intended to refer to an aryl group attached through a C₁-C₄ alkyl bridge to the residue of the indicated compound; the term "(C₁-C₃ alkyl)aryl" is intended to refer to a C₁ -C₃ alkyl group which isattached through an aryl ring to the residue of the indicated compound;the term "aryl(C₁ -C₃ alkyl)" is intended to refer to an aryl groupattached through a C₁ -C₃ alkyl group to the residue of the indicatedcompound.

As used herein, "carbocycle" or "carbocyclic residue" is intended tomean any stable 3- to 7-membered monocyclic or bicyclic or 7- to14-membered bicyclic or tricyclic or an up to 26-membered polycycliccarbon ring, any of which may be saturated, partially unsaturated, oraromatic. Examples of such carbocyles include, but are not limited to,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl,indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term "heterocycle" is intended to mean a stable 5-to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclicheterocyclic ring which is either saturated or unsaturated, and whichconsists of carbon atoms and from 1 to 4 heteroatoms independentlyselected from the group consisting of N, O and S and wherein thenitrogen and sulfur heteroatoms may optionally be oxidized, and thenitrogen may optionally be quaternized, and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The heterocyclic ring may be attached to its pendant groupat any heteroatom or carbon atom which results in a stable structure.The heterocyclic rings described herein may be substituted on carbon oron a nitrogen atom if the resulting compound is stable. Examples of suchheterocycles include, but are not limited to, pyridinyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thiophenyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl,xanthenyl, phenoxathiinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl,pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl,1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl,carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl,phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl,pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl,quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl,benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also includedare fused ring and spiro compounds containing, for example, the aboveheterocycles. Preferred heterocycles include, but are not limited to,pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl,benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl,benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl.

When a bond to a substituent is shown to cross the bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. For example, when the substituent is piperazinyl,piperidinyl, or tetrazolyl, unless specified otherwise, saidpiperazinyl, piperidinyl, tetrazolyl group may be bonded to the rest ofthe compound of a given formula via any atom in such piperazinyl,piperidinyl, tetrazolyl group.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. By stable compound orstable structure it is meant herein a compound that is sufficientlyrobust to survive isolation to a useful degree of purity from a reactionmixture, and formulation into an efficacious therapeutic agent.

The term "amino acid" as used herein means an organic compoundcontaining both a basic amino group and an acidic carboxyl group.Included within this term are natural amino acids, modified and unusualamino acids, as well as amino acids which are known to occurbiologically in free or combined form but usually do not occur inproteins. Included within this term are modified and unusual aminoacids,such as those disclosed in, for example, Roberts and Vellaccio(1983) The Peptides, 5: 342-429, the teaching of which is herebyincorporated by reference. Modified or unusual amino acids which can beused to practice the invention include, but are not limited to, D-aminoacids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid,ornithine, 2,4-diaminobutyric acid, homoarginine, norleucine,N-methylaminobutyric acid, naphthylalanine, phenylglycine,β-phenylproline, tert-leucine, 4-aminocyclohexylalanine,N-methylnorleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine,N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid,6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid,2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylicacid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoicacid.

The term "amino acid residue" as used herein means that portion of anamino acid (as defined herein) that is present in a peptide.

The methods of the present invention may be further understood byreference to Scheme 1. ##STR29##

It is the object of the present invention to provide an improved processfor the preparation of diamine intermediates for the synthesis of HIVprotease inhibitors including cyclic carbonyls.

Step 1: Diamide Formation: Preparation of Compound of Formula (II)

This step comprises: (a) the conversion of a compound of formula (I) toa bisamide using an carboxyl activating agent by reacting a compound offormula (I) in a suitable solvent, preferably an aprotic solvent, at asuitable temperature with preferably at least about two molarequivalents (more preferably 2-100 or 2-20 equivalents) of a suitablecarboxyl activating agent for a suitable length of time, followed by;(b) treatment of the activated acyl intermediate with at least about twomolar equivalents (more preferably 2-100 or 2-20 equivalents) of aN,O-dialkylhydroxylamine of formula R⁶ NHOR⁵ to form a compound offormula (II). By way of general guidance, in step (Ia), compound (I) inan aprotic solvent may be contacted, with agitation at 0° to 100° C. for1-24 hr under an inert atmosphere, with 2-3 molar equivalents of acarboxylic acid activating agent, followed by step (1b), treatment insitu of the resulting intermediate with a N,O-dialkylhydroxylamine at0°-50° C. for 1-24 hr to form compound (II). Compound (II) may beseparated from the reaction mixture, for example, by washing with diluteacid and water and concentrating the organic layer. Compound (II)optionally may be recrystallized from a suitable solvent mixture, suchas ethyl acetate/hexane, prior to use in step (2).

A preferred reaction temperature for step (1) is 25° C.

A preferred reaction time for step (1a) is about 5-7 hr and for step(1b) is about 12-18 hr.

Preferred solvents for step (1) include methylene chloride,tetrahydrofuran, N,N-dimethylformamide, and dimethoxyethane. A morepreferred solvent is methylene chloride.

Preferred carboxyl activating agents for step (1) include1,1'-carbonyldiimidazole, thionyl chloride, oxalyl chloride,isobutylchloroformate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride. A more preferred carboxyl activating agent is1,1'-carbonyldiimidazole.

A preferred N,O-dialkylhydroxylamine is N,O-dimethylhydroxylaminehydrochloride.

Step (2): Ketone Formation: Preparation of Compound of Formula (III)

This step comprises alkylation of the amide carbonyl of a compound offormula (II) by contacting a compound of formula (II) in a suitablesolvent, preferably an aprotic solvent, with preferably at least abouttwo equivalents (more preferably 2-100 or 2-20 equivalents) of anucleophilic organometallic reagent, said nucleophilic organometallicreagent being suitable for the addition of a R⁴ - or R⁷ - substituent toamides of the structure of compound (II), at a suitable temperature, toform a compound of formula (III). Alkylation of the amide carbonyl maybe carried out using an organometallic reagent of the formula R⁴ --Mand/or R⁷ --M, where M is a suitable metal halide, such as lithium ormagnesium halide. By way of general guidance, compound (II) in asuitable aprotic solvent at -78°-100° C. may be contacted with 2-10molar equivalents of a nucleophile, R⁴ --M and/or R⁷ --M, for 0.1-24 hrto form compound (III). Compound (III) may be isolated by washing thisreaction mixture with dilute acid and concentrating the organic layer.Compound (III) may optionally be purified by chromatography on silicagel prior to use in step (3).

A preferred reaction temperature is 0° C.

Preferred reaction solvents include tetrahydrofuran, ether, or hexanes.A more preferred solvent is tetrahydrofuran.

It is preferred that 3-6 molar equivalents of nucleophilicorganometallic reagent R⁴ --M or R⁷ --M is used. The preferrednucleophilic organometallic reagent is an organolithium ororganomagnesium halide (i.e., M is lithium or magnesium halide.Preferred nucleophilic organometallic reagents include benzyllithium,n-butyllithium, sec-butyllithium, tert-butyllithium, methylmagnesiumbromide, octylmagnesium bromide, hexylmagnesium bromide, vinyllithium,allyllithium, ethyllithium, phenylthiomethyllithium, 2-furyllithium,butynyllithium, benzylmagnesium chloride, and phenylmagnesium chloride,and subsituted derivatives thereof. It is preferred that 4-7 molarequivalents of R⁴ and/or R⁷ be used.

Step (3): Oxime Formation: Preparation of Compound of Formula (IV)

This step comprises reacting a ketone compound of formula (III) in asuitable solvent, preferably a protic solvent, for a sufficient periodof time at a suitable temperature, with preferably at least about twoequivalents (more preferably 2-100 or 2-20 equivalents) of anhydroxylamine of formula NH₂ OR³, to form an oxime compound of formula(IV). Said hydroxylamine is preferably an acid salt, and more preferablyis a hydroxlamine hydrochloride. By way of general guidance, compound(III) in a polar protic solvent may be contacted with agitation at 0° to100° C. with an hydroxylamine for 1-48 hr to form compound (IV).Compound (IV) may be isolated by extracting the reaction mixture with anorganic solvent, such as ethyl acetate, and concentrating the organiclayer. The residue may optionally be purified by chromatography onsilica gel to give predominantly the anti:anti oxime isomer for use instep (4).

A preferred reaction temperature is about 25° C.

A preferred reaction time is 24 hr.

Preferred solvents include water, methanol and ethanol. A more preferredsolvent is aqueous ethanol.

A preferred hydroxylamine is hydroxylamine hydrochloride.

The reaction in step (3) is optionally, but preferably carried out inthe absence of a base. For example, when sodium acetate was added toneutralize the acid evolved, significantly greater amounts of theundesired oxime isomers resulted.

Step (4): Amine Formation: Preparation of Compound of Formula (V)

This step comprises contacting an oxime compound of formula (IV) in asuitable solvent for a sufficient period of time at a suitabletemperature with a suitable reducing agent to effect the conversion ofthe oxime groups in the compound of formula (IV) to amine groups, toobtain a compound of formula (V). By way of general guidance, compound(IV) in a suitable solvent may be contacted with agitation at about -10°to 100 ° C. for about 0.1-72 hr with a reducing agent to form compound(V) which can be optionally isolated in the free base or salt form.

Preferred reducing agents include lithium aluminum hydride, borane,diisobutoxyaluminum hydride, or catalytic hydrogenation in the presenceof a Raney nickel catalyst. A more preferred reducing agent isdiisobutoxyaluminum hydride.

The suitable solvent will depend on the choice of reducing agent.Preferred solvents for diisobutyoxyaluminum hydride reduction includetetrahydrofuran, ether, or toluene. A more preferred solvent for thisreagent is toluene. If catalytic hydrogenation over Raney nickel ischosen, then the preferred solvent includes ethanol.

A preferred reaction temperature is 25°-35° C.

A preferred reaction time is about 18 hr.

A preferred isolation method when the reducing agent isdiisobutoxyaluminum hydride and the reaction solvent is toluene isstirring the reaction mixture with saturated sodium potassium tartrateand extraction with an organic solvent, for example ethyl acetate, andconcentrating the organic layer. The residue can be optionally purifiedby chromatography on silica gel to give the diamine (V) with the desired(R,S,S,R) stereochemistry.

The synthetic processes of the present invention can be employed for thesynthesis of HIV protease inhibitors such as those disclosed in Jadhavet al., WO 93/07,128 and European Patent Application 402,646 A1. Thedisclosure of each of the references cited herein is hereby incorporatedherein by reference.

The present invention may be further exemplified by reference to Scheme2. ##STR30##

With a judicious selection of reagents, as is well appreciated to oneskilled in the art of organic synthesis, the claimed process can beperformed in a straightforward manner to yield the compounds of formulas(II), (III), (IV) and (V).

Each of the references cited herein are hereby incorporated herein byreference.

The following examples are meant to be illustrative of the presentinvention. These examples are presented to exemplify the invention andare not to be construed as limiting the invention's scope.

EXAMPLE 1 (Formula (II) Wherein R¹, R², R⁵, and R⁶ =Methyl)

Step 1

To a solution of L-2,3-isopropylidene tartaric acid (30 g, 157.8 mmol)in methylene chloride (1 L) was added 1,1'-carbonyldiimidazole (60 g,370.0 mmol). After stirring for 6 hr, of N,O-dimethylhydroxylaminehydrochloride (34.0 g, 350 mmol) was added and the resulting solutionwas stirred overnight. The solvent was partially removed under reducedpressure and the residue was diluted with ethyl acetate, The solutionwas then acidified with 4N HCl, saturated with NaCl, and extracted withEtOAc. The combined organic layers were washed with brine and dried overMgSO₄. The solvent was removed under reduced pressure and the residuewas triturated with ethyl acetate and hexanes to give the bis-Weinrebamide (II) (35.6 g, 82%) as a white solid. mp. 78°-80° C. ¹ H NMR (300MHz, CDCl₃) δ 5.16 (s, 2H, CH), 3.70 (s, 6H, OCH₃), 3.22 (s, 6H, CH₃),1.52 (s, 6H, CH₃); MS (CI,NH₃) m/e 277 (M+1).

EXAMPLE 2 (Formula (III) Wherin R¹ and R² Methyl, R⁵, and R⁶ =Octyl)

Step 2

To a solution of the product of Example 1 (4.0 g, 14.5 mmol) in THF (100mL) was added a solution of 2M octylmagnesium bromide in THF (20 mL, 40mmol) dropwise. After stirring for 3.5 hr, the solution was quenchedwith saturated NH₄ Cl, acidified with 1N HCl, and was extracted withEtOAc. The combined organic layers were washed with brine and dried overMgSO₄. The solvent was removed under reduced pressure and the residuewas chromatographed on silica gel. Elution with 7.5% ethyl acetate inhexanes gave the bis-octyl ketone (III) (4.86 g, 88%) as an oil. ¹ H NMR(300 MHz, CDCl₃) δ 4.55 (s, 2H, CH), 2.64 (dt, 4H, CH₂), 1.62 (m, 4H,CH₂), 1.42 (s, 6H, CH₃), 1.27 (broad s, 20H, CH₂), 0.88 (t, 6H, CH₃); MS(CI,NH₃) m/e 383 (M+1).

EXAMPLE 3 (Formula (IV) Wherein R¹ and R² =Methyl, R⁵, and R⁶ =Octyl, R³=H)

Step 3

To a solution of the product of Example 2 (4.65 g, 12.2 mmol) in ethanol(140 mL) and water (35 ml) was added hydroxylamine hydrochloride (2.22g, 32.2 mmol). After stirring overnight, the solvent was partiallyremoved under reduced pressure, and the residue was diluted with waterand extracted with EtOAc. The combined organic layers were washed withbrine and dried over MgSO₄. The solvent was removed under reducedpressure and the residue was chromatographed on silica gel. Elution with15% ethyl acetate in hexanes gave the bis-octyl oxime (IV) as a 4.5/1mixture of the anti:anti/anti:syn oxime isomers (3.76 g, 75%). anti:antioxime; ¹ H NMR (300 MHz, CDCl₃) δ 4.55 (s, 2H, CH), 2.47 (m, 2H, CH₂),2.23 (m, 2H, CH₂), 1.59 (br s, 4H, CH₂), 1.43 (s, 6H, CH₃), 1.26 (broads, 20H, CH₂), 0.88 (t, 6H, CH₃); MS (CI,NH₃) m/e 413 (M+1).

EXAMPLE 4 (Formula (V) Wherein R¹ and R² =Methyl, R⁵ and R⁶ =Octyl)

Step 4

To a solution of the the product of Example 3 (3.68 g, 8.9 mmol) intoluene (70 mL) at 0° C. was added a solution of 1.5M diisobutylaluminumhydride in toluene (53 mL, 80 mmol) over 15 min. The resulting solutionwas allowed to warm to room temperature. After stirring overnight, thesolution was quenched with saturated Rochelle's salt and gently stirredat room temperature. After stirring overnight, the solution wasextracted with EtOAc and dried over MgSO₄. The solvent was removed underreduced pressure and the residue was chromatographed on silica gel.Elution with 10% methanol in methylene chloride gave the (R,S,S,R)diamine V (2.33 g, 68%) as an oil. ¹ H NMR (300 MHz, CDCl₃) δ 3.80 (s,2H, CH), 2.68 (m, 2H, CH), 1.43 (m, 4H, CH₂), 1.41 (s, 6H, CH₃), 1.27(broad s, 24H, CH₂), 0.88 (t, 6H, CH₃); MS (CI,NH₃) m/e 385 (M+1).

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof and,accordingly, reference should be made to the appended claims as furtherindicating the scope of the invention.

What is claimed is:
 1. A compound of formula (II): ##STR31## wherein: R⁵and R⁶ are independently C₁ -C₄ alkyl or benzyl; andR¹ and R² areindependently: H, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₆ -C₁₀ aryl, C₇ -C₁₄arylalkyl, C₁ -C₄ haloalkyl, C₃ -C₇ cycloalkyl, or can be taken togetherto be keto, or, alternatively, R¹ and R² can be taken together with thecarbon to which they are attached to form a 3-7 membered saturatedcarbocyclic ring system.
 2. A compound of claim 1 wherein:R⁵ and R⁶ areindependently C₁ -C₄ alkyl or benzyl; and R¹ and R² are independentlymethyl, or ethyl, or, alternatively, R¹ and R² can be taken togetherwith the carbon to which they are attached to form cyclopentyl.